CLEANING VALIDATION

PRINCIPLE
1.1
Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential.
1.2
Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients (APIs). In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level.
1.3
Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment that is suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs).
1.4
The objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.
2.
PURPOSE AND SCOPE
2.1
These guidance notes describe the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants.
2.2
These guidance notes apply to the manufacture of pharmaceutical products (final dosage forms) and of active pharmaceutical ingredients (APIs).
3.
GENERAL
3.1
Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc.
3.2
Cleaning procedures for product changeover in the case of marketed products should be fully validated.
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3.3
Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.
3.4
Several questions should be addressed when evaluating the cleaning process. For example:
-
At what point does a piece of equipment or system become clean?
-
What does ‘visually clean’ mean?
-
Does the equipment need to be scrubbed by hand?
-
What is accomplished by hand scrubbing rather than just a solvent wash?
-
How variable are manual cleaning processes from batch to batch and product to product?
-
What is the most appropriate solvent or detergent?
-
Are different cleaning processes required for different products in contact with a piece of equipment?
-
How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
3.5
Cleaning procedures for products and processes, which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program, which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".
3.6
At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
3.7
Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.
3.8
Control of change to validated cleaning procedures is required. Re-validation should be considered under the following circumstances:
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3.8.1
Re-validation in cases of changes to equipment, products or processes; and
3.8.2
Periodic re-validation at defined intervals.
3.9
Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.
3.10
It is usually not considered acceptable to "test until clean". This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of "test until clean" should not be required. The practice of "test until clean" is not considered to replace the need to validate cleaning procedures.
3.11
Products that simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.
4.
DOCUMENTATION
4.1
A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following:
-
The objective of the validation process;
-
Responsibilities for performing and approving the validation study;
-
Description of the equipment to be used;
-
The interval between the end of production and the beginning of the cleaning procedures;
-
Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment;
-
The number of cleaning cycles to be performed consecutively;
-
Any routine monitoring equipment;
-
Sampling procedures, including the rationale for why a certain sampling method is used;
-
Clearly defined sampling locations;
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Data on recovery studies where appropriate;
-
Analytical methods including the limit of detection and the limit of quantitation of those methods;
-
The acceptance criteria, including the rationale for setting the specific limits;
-
Other products, processes, and equipment for which the planned validation is valid according to the “bracketing” concept; and
-
When Re-validation will be required.
4.2
The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports.
4.3
A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by the Plant Management.
4.4
The cleaning process should be documented in an SOP.
4.5
Records should be kept of cleaning performed in such a way that the following information is readily available:
-
The area or piece of equipment cleaned;
-
The person who carried out the cleaning;
-
When the cleaning was carried out;
-
The SOP defining the cleaning process; and
-
The product, which was previously processed on the equipment being cleaned.
4.6
The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance.
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5.
PERSONNEL
5.1
Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.
5.2
It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals.
6.
EQUIPMENT
6.1
The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.
6.2
Dedicated equipment should be used for products, which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).
7.
MICROBIOLOGICAL ASPECTS
7.1
The existence of conditions favorable to reproduction of micro-organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.
7.2
The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.
7.3
In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.
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8.
SAMPLING
8.1
Samples should be drawn according to the Cleaning Validation Protocol.
8.2
There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
A.
Direct Surface Sampling
(i) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.
B.
Rinse Samples
(i)
Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant.
(ii)
A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.
9.
DETERGENTS
9.1
The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures.
9.2
The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.
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10.
ANALYTICAL METHODS
10.1
The analytical methods should be validated before the Cleaning Validation Study is carried out.
10.2
The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.
10.3
The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.
11.
ESTABLISHMENT OF LIMITS
11.1
The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.
11.2
The approach for setting limits can be:
-
product specific Cleaning Validation for all products,
-
grouping into product families and choosing a ‘worst-case’ product,
-
grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).
11.3
Carry-over of product residues should meet defined criteria. For example, the most stringent of the following three criteria:
(a)
No more than 0.1%of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
(b)
No more than 10ppm of any product will appear in another product,
(c)
No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,
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(d)
For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
11.4
One cannot ensure that the contaminate will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.
11.5
In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.
12.
REFERENCE
12.1 PIC/S document, PI 006-3: Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation.
END OF DOCUMENT

MASTER PLAN

An Overview of Pharmaceutical Validation and Process Controls in Drug Development

Abstract
It has always been known that facilities and processes involved in pharmaceutical production
impact significantly on the quality of the products. The processes include raw material and
equipment inspections as well as in-process controls. Process controls are mandatory in good
manufacturing practice (GMP). The purpose is to monitor the on-line and off-line performance
of the manufacturing process, and hence, validate it. Thus validation is an integral part of
quality assurance.
This overview examines the need for pharmaceutical validation, the various approaches and
steps involved, and other pertinent considerations.
Keywords: Drug production, pharmaceutical validation, pharmaceutical process control.
1Present address: Pharmacy Department, National Hospital, Abuja, Nigeria
2To whom correspondence should be addressed: E-mail: okhamafe@uniben.edu
E Jatto & AO Okhamafe
Trop J Pharm 116 Res, December 2002; 1 (2)
Introduction
The development of a drug product is a
lengthy process involving drug discovery,
laboratory testing, animal studies, clinical
trials and regulatory registration. To further
enhance the effectiveness and safety of the
drug product after approval, many regulatory
agencies such as the United States Food
and Drug Administration (FDA) also require
that the drug product be tested for its
identity, strength, quality, purity and stability
before it can be released for use. For this
reason, pharmaceutical validation and
process controls are important in spite of the
problems that may be encountered1.
Process controls include raw materials
inspection, in-process controls and targets
for final product. The purpose is to monitor
the on-line and off-line performance of the
manufacturing process and then validate it.
Even after the manufacturing process is
validated, current good manufacturing
practice also requires that a well-written
procedure for process controls is established
to monitor its performance2.
This paper provides an overview of
pharmaceutical validation and process
controls in drug development. The validation
concept can be applied to new drugs, new
dosage forms and generic drug
development.
Essentials of Pharmaceutical Validation
Validation is an integral part of quality
assurance; it involves the systematic study
of systems, facilities and processes aimed at
determining whether they perform their
intended functions adequately and
consistently as specified. A validated
process is one which has been
demonstrated to provide a high degree of
assurance that uniform batches will be
produced that meet the required
specifications and has therefore been
formally approved. Validation in itself does
not improve processes but confirms that the
processes have been properly developed
and are under control3. Adequate validation
is beneficial to the manufacturer in many
ways3:
· It deepens the understanding of
processes; decreases the risk of
preventing problems and thus assures
the smooth running of the process.
· It decreases the risk of defect costs.
· It decreases the risk of regulatory noncompliance.
· A fully validated process may require
less in-process controls and endproduct
testing.
Validation should thus be considered in the
following situations:
· Totally new process;
· New equipment;
· Process and equipment which have
been altered to suit changing priorities;
and
· Process where the end-product test is
poor and an unreliable indicator of
product quality.
When any new manufacturing formula or
method of preparation is adopted, steps
should be taken to demonstrate its suitability
for routine processing. The defined process
should be shown to yield a product
consistent with the required quality. In this
phase, the extent to which deviations from
chosen parameters can influence product
quality should also be evaluated. When
certain processes or products have been
validated during the development stage, it is
not always necessary to revalidate the whole
process or product if similar equipment is
used or similar products have been
produced, provided that the final product
conforms to the in-process controls and final
product specification. There should be a
clear distinction between in-process control
and validation. In production, tests are
performed each time on a batch to batch
basis using specifications and methods
devised during the development phase. The
objective is to monitor the process
continuously4.
E Jatto & AO Okhamafe
Trop J Pharm 117 Res, December 2002; 1 (2)
Major Phases in Validation
The activities relating to validation studies
may be classified into three:
Phase 1: This is the Pre-validation
Qualification Phase which covers all
activities relating to product research and
development, formulation pilot batch studies,
scale-up studies, transfer of technology to
commercial scale batches, establishing
stability conditions and storage, and handling
of in-process and finished dosage forms,
equipment qualification, installation
qualification, master production document,
operational qualification and process
capacity.
Phase 2: This is the Process Validation
Phase. It is designed to verify that all
established limits of the critical process
parameter are valid and that satisfactory
products can be produced even under the
worst conditions.
Phase 3: Known as the Validation
Maintenance Phase, it requires frequent
review of all process related documents,
including validation of audit reports, to
assure that there have been no changes,
deviations, failures and modifications to the
production process and that all standard
operating procedures (SOPs), including
change control procedures, have been
followed. At this stage, the validation team
comprising of individuals representing all
major departments also assures that there
have been no changes/deviations that
should have resulted in requalification and
revalidation5. A careful design and validation
of systems and process controls can
establish a high degree of confidence that all
lots or batches produced will meet their
intended specifications. It is assumed that
throughout manufacturing and control,
operations are conducted in accordance with
the principle of good manufacturing practice
(GMP) both in general and in specific
reference to sterile product manufacture.
The validation steps recommended in GMP
guidelines can be summarized as follows5:
· As a pre-requisite, all studies should
be conducted in accordance with a
detailed, pre-established protocol or
series of protocols, which in turn is
subject to formal – change control
procedures;
· Both the personnel conducting the
studies and those running the process
being studied should be appropriately
trained and qualified and be suitable
and competent to perform the task
assigned to them;
· All data generated during the course of
studies should be formally reviewed
and certified as evaluated against
pre-determined criteria;
· Suitable testing facilities,
equipment, instruments and
methodology should be available;
· Suitable clean room facilities should
be available in both the ‘local’ and
background environment. There
should be assurance that the clean
room environment as specified is
secured through initial commissioning
(qualification) and subsequently
through the implementation of a
programme of re-testing – in-process
equipment should be properly
installed, qualified and maintained;
· When appropriate attention has been
paid to the above, the process, if
aseptic, may be validated by means of
“process simulation” studies;
· The process should be revalidated at
intervals; and
· Comprehensive documentation
should be available to define support
and record the overall validation
process.
Protocols should specify the following in
detail6:
· The objective and scope of study.
There should already be a definition of
purpose;
· A clear and precise definition of
process equipment system or subsystem,
which is to be the subject of
E Jatto & AO Okhamafe
Trop J Pharm 118 Res, December 2002; 1 (2)
study with details of performance
characteristics;
· Installation and qualification
requirement for new equipment;
· Any upgrading requirement for existing
equipment with justification for the
change(s) and statement of
qualification requirement;
· Detailed stepwise statement of actions
to be taken in performing the study (or
studies);
· Assignment of responsibility for
performing the study;
· Statement on all test methodology to
be employed with a precise statement
of the test equipment and/or materials
to be used;
· Test equipment calibration requirements;
· References to any relevant standard
operating procedures (SOP);
· Requirement for the current format of
the report on the study;
· Acceptance criteria against which the
success (or otherwise) of the study is
to be evaluated; and
· The personnel responsible for
evaluating and certifying the acceptability
of each stage in the study and
for the final evaluation and certification
of the process as a whole, as
measured against the pre-defined
criteria.
All personnel involved in conducting the
studies should be properly trained and
qualified because they can, and often, have
a crucial effect on the quality of the endproduct.
All information or data generated as
a result of the study protocol should be
evaluated by qualified individuals against
protocol criteria and judged as meeting or
failing the requirements. Written evidence
supporting the evaluation and conclusion
should be available. If such an evaluation
shows that protocol criteria have not been
met, the study should be considered as
having failed to demonstrate acceptability
and the reasons should be investigated and
documented. Any failure to follow the
procedure as laid down in the protocol must
be considered as potentially compromising
the validity of the study itself and requires
critical evaluation of all the impact on the
study. The final certification of the validation
study should specify the pre-determined
acceptance criteria against which success or
failure was evaluated5.
Validation of Analytical Assays and Test
Methods
Method validation confirms that the analytical
procedure employed for a specific test is
suitable for its intended use. The validation
of an analytical method is the process by
which it is established by laboratory studies
that the performance characteristics of the
method meet the requirement for the
intended application. This implies that
validity of a method can be demonstrated
only though laboratory studies7. Methods
should be validated or revalidated8, 9:
· before their introduction and routine
use;
· whenever the conditions change for
which the method has been validated,
e.g., instrument with different
characteristics; and
· wherever the method is changed and
the change is outside the original
scope of the method.
Strategy for Validation of Methods
The validity of a specific method should be
demonstrated in laboratory experiments
using samples or standards that are similar
to the unknown samples analyzed in the
routine. The preparation and execution
should follow a validation protocol preferably
written in a step-by-step instruction format as
follows10:
· Develop a validation protocol or
operating procedure for the validation;
· Define the application purpose and
scope of the method;
E Jatto & AO Okhamafe
Trop J Pharm 119 Res, December 2002; 1 (2)
· Define the performance parameters
and acceptance criteria;
· Define validation experiments;
· Verify relevant performance characteristics
of the equipment;
· Select quality materials, e.g.,
standards and reagents;
· Perform pre-validation experiments;
· Adjust method parameters and/or
acceptance criteria, if necessary;
· Perform full internal (and external)
validation experiments;
· Develop SOPs for executing the
method routinely;
· Define criteria for revalidation;
· Define type and frequency of system
suitability tests and/or analytical quality
control (AQC) checks for the routine;
and
· Document validation experiments and
results in the validation report.
Environmental Considerations: Cleaning
and Clean Room Standards
Cleaning validation is documented proof that
one can consistently and effectively clean a
system or equipment items. The procedure
is necessary for the following reasons11, 12:
· It is a customer requirement – it
ensures the safety and purity of the
product;
· It is a regulatory requirement in active
pharmaceutical product manufacture;
and
· It also assures from an internal control
and compliance point of view the
quality of the process.
The FDA guide to inspections13 intended to
cover equipment cleaning (chemical
residues only) expects firms to have written
procedure (SOPs) detailing the cleaning
processes and also written general
procedure on how cleaning processes will be
validated. FDA expects a final validation
report which is approved by management
and which states whether or not the cleaning
process is valid. The data should support a
conclusion that residues have been reduced
to an “acceptable level”14. Harder14 cited five
crucial elements:
1. A standard operating procedure (SOP)
for cleaning with a checklist;
2. A procedure for determining cleanliness
(rinse or swab);
3. An assay for testing residual drug
levels;
4. Pre-set criteria for testing chemical
and microbial limit to which to
equipment must be cleaned; and
5. Protocol for cleaning validation.
Harder14 recommended that the procedure
be tested for, requiring it to be successful on
three successive cleanings and there should
be periodic revalidation as well as
revalidation after significant changes.
Jenkins and Vanderwielen15 presented an
overview of cleaning validation covering
strategy and determination of residue limits,
method of sampling and analysis noting that
“increased use of multi-purpose equipment”
has produced increased interest in cleaning
validation. The cleaning protocol must be
thorough and must be checked. Training is
essential. A validation program requires
· criteria for acceptance after cleaning,
· appropriate methods of sampling,
· a maximum limit set for residues, and
· test methods that must themselves be
tested.
Products to be tested may be put into groups
rather than testing all of them16. The most
important may not be the highest volume
product but those capable of causing the
largest possible problems if contaminated or
if they contaminate the products (solubility of
the drug is an important issue). Equipment
may also be tested in groups.
Process Validation
Process validation is the means of ensuring
and providing documentary evidence that
processes (within their specified design
E Jatto & AO Okhamafe
Trop J Pharm 120 Res, December 2002; 1 (2)
parameters) are capable of repeatedly and
reliably producing a finished product of the
required quality5. It would normally be
expected that process validation be
completed prior to the release of the finished
product for sale (prospective validation).
Where this is not possible, it may be
necessary to validate processes during
routine production (concurrent validation).
Processes, which have been in use for some
time without any significant changes, may
also be validated according to an approved
protocol (retrospective validation)10-17.
Pre-requisites for Process Validation
Before process validation can be started,
manufacturing equipment and control
instruments as well as the formulation must
be qualified. The information on a
pharmaceutical product should be studied in
detail and qualified at the development
stage, i.e., before an application for
marketing authorization is submitted. This
involves studies on the compatibility of active
ingredients and recipients, and of final drug
product and packaging materials, stability
studies, etc. Other aspects of manufacture
must be validated including critical services
(water, air, nitrogen, power supply, etc.) and
supporting operations such as equipment
cleaning and sanitation of premises. Proper
training and motivation of personnel are prerequisites
to successful validation18-20.
The Pharmaceutical Process Equipment
The key idea of validation is to provide a
high level of documented evidence that the
equipment and the process conform to a
written standard. The level (or depth) is
dictated by the complexity of the system or
equipment. The validation package must
provide the necessary information and test
procedures required to provide that the
system and process meet specified
requirements21. Validation of pharmaceutical
process equipment involves the following10:
· Installation Qualification: This
ensures that all major processing and
packaging equipment, and ancillary
systems are in conformity with
installation specification, equipment
manuals schematics and engineering
drawing. It verifies that the equipment
has been installed in accordance with
manufacturers recommendation in a
proper manner and placed in an
environment suitable for its intended
purpose.
· Operational Qualification: This is
done to provide a high degree of
assurance that the equipment
functions as intended. Operational
qualification should be conducted in
two stages:
· Component Operational Qualification,
of which calibration can
be considered a large part.
· System Operational Qualification
to determine if the entire
system operates as an integrated
whole.
· Process Performance Qualification:
This verifies that the
system is repeatable and is
consistently producing a quality
product14.
These exercises assure, through appropriate
performance lists and related documentation,
that equipment, ancillary systems and
sub-systems have been commissioned
correctly. The end results are that all future
operations will be reliable and within
prescribed operational limits.
At various stages in a validation exercise
there are needs for protocols, documentation,
procedures, specifications and
acceptance criteria for test results. All these
need to be reviewed, checked and
authorized. It would be expected that
representatives from the professional
disciplines, e.g., engineering, research and
development, manufacturing, quality control
and quality assurance are actively involved
in these undertakings with the final
authorization given by a validation team or
the quality assurance representative22.
E Jatto & AO Okhamafe
Trop J Pharm 121 Res, December 2002; 1 (2)
Approaches to Validation Process
There are two basic approaches to the
validation of the process itself (apart from the
qualification of equipment used in
production, the calibration of control and
measurement instruments, the evaluation of
environmental factors, etc). These are the
experimental approach and the approach
based on the analysis of historical data. The
experimental approach, which is applicable
to both prospective and concurrent
validation, may involve23
· extensive product testing,
· simulation process trials,
· challenge/worst case trials, and
· control of process parameters (mostly
physical).
One of the most practical forms of process
validation, mainly for non-sterile products, is
the final testing of the product to the extent
greater than that required in routine quality
control. It may involve extensive sampling,
far beyond that called for in routine quality
control and specifications, and often for
certain parameters only. Thus, for instance,
several hundred tablets per batch may be
weighed to determine unit dose uniformity.
The results are then treated statistically to
verify the normality of the distribution and to
determine the standard deviation from the
average weight. Confidence limits for
individual results and for batch homogeneity
are also estimated. Strong assurance is
provided that samples taken at random will
meet regulatory requirements if the
confidence limits are within compendial
specifications24.
In the approach based on analysis of
historical data, no experiments are
performed in retrospective validation, but
instead all available historical data
concerning a number of batches are
combined and jointly analysed, if production
is proceeding smoothly during the period
preceding validation and the data in
process inspection and final testing of the
product are combined and treated
statistically. The results including the
outcome of process capability studies, trend
analysis, etc., will indicate whether the
process is under control or not.
Expert Evaluation
This is an evaluation of the entire study
against the protocol requirements as outlined
above. It should be prepared and the
conclusion drawn at each stage stated. The
final conclusions should reflect whether the
protocol requirements were met. The
evaluation should include an assessment of
the planned calibration and maintenance
programmes for the equipment and
instrumentation to maintain the validated
conditions. In addition, all process monitoring
and control procedures required to routinely
ensure that the validated conditions are
maintained should be reported. The
evaluation should be signed by authorized
officers of the organization who were
members of the team establishing the
protocol and who have appropriate expertise
in the area assigned to them. Overall
approval of the study should be authorized
by the head of the validation team and the
head of the quality control department21.
The Validation Report
A written report should be available after
completion of the validation. If found
acceptable, it should be approved and
authorized (signed and dated). The report
should include at least the following4:
· Title and objective of study;
· Reference to protocol;
· Details of material;
· Equipment;
· Programmes and cycles used;
· Details of procedures and test
methods;
· Results (compared with acceptance
criteria); and
· Recommendations on the limit and
criteria to be applied on future basis.
E Jatto & AO Okhamafe
Trop J Pharm 122 Res, December 2002; 1 (2)
Conclusion
It is necessary, before approval of a new
drug, that an accurate and reliable
assessment for its effectiveness and safety
for the intended indication and target patient
population is demonstrated. Pharmaceutical
validation which includes assay validation,
cleaning validation, equipment validation as
well as the overall process validation is
crucial in stability analysis, animal studies
and early phases of clinical development
such as bioavailability/bioequivalence
studies. After the drug is approved,
pharmaceutical validation and process
control are necessary to ensure that the drug
product will meet/set pharmaceutical
standards for identity, strength, quality,
purity, stability, evaluation safety and
efficacy.
In general, pharmaceutical validation and
process control provide a certain assurance
of batch uniformity and integrity of the
product manufactured.
References
1. Sharp JR. The Problems of Process Validation.
Pharm J 1986; 1:43-5.
2. Chow S. Pharmaceutical Validation and Process
Controls in Drug Development. Drug Inf J 1997;
31: 1195-201.
3. Committee on Specifications for Pharmaceutical
Preparations. Good Manufacturing Practices for
Pharmaceutical Products. WHO Technical
Report Series no. 82. Geneva: World Health
Organization, 1992, pp 14-79.
4. South African Guide to Good Manufacturing
Practice. Pretoria: Medicines Control Council,
1996. http://www.pharmanet.co.za/mcc
/inpectorate/ins-71998.htm.
5. Guide to Inspections of Oral Solid Dosage Forms
Pre/Post Approval Issued for Development and
Validation. Washington DC: US Food and Drug
Administration, 1994.
6. Therapeutics Products Programme. Process
Validation: Aseptic Processes for
Pharmaceuticals. http://www.hc-sc.gc.ca/hpbdgps/
therapeutic; downloaded March 30, 2001.
7. Validation of Compendia Methods. United States
Pharmacopoeia and National Formulary XVIII,
Rockville, MD: The United States Pharmacopoeia
Convention, Inc., 1995, pp. 1612-710.
8. Validation of Analysis Procedures. International
Conference on Harmonization (ICH) of Technical
Requirements for the Registration of Pharmaceuticals
for Human Use. Geneva: ICH-QZA, 1995.
9. Green JM. A Practical Guide to Analytical Method
Validation, Anal. Chem. News and Features
1996; 60:305A-9A.
10. Rosendale DM. Process Equipment 1990.
http:/www.vectorcorporation.com/download/val_in
terphex.
11. Cleaning Validation in Active Pharmaceutical
Ingredient Manufacturing Plants. Brussels: Active
Pharmaceutical Ingredients Committee.
http://www.apic.cefic.org/pub4cleaningval/1999pd
f; downloaded September 1999.
12. Guide to Inspections Validation of Cleaning
Processes. Washington DC: US Food and Drug
Administration. http://www.fda.gov/ora/inspect
_ref/igs/valid.html.
13. Cleaning Validation Guidelines. Ottawa, Canada:
Health Products and Food Branch Inspectorate,
Health Canada, May 2000, p 11.
14. Harder SW. The Validation of Cleaning Procedures.
Pharm Technol 1984; 8(5): 29-34.
15. Jenkins KM, Vanderwielen AJ. Cleaning Validation:
An Overall Perspective. Pharm Technol 1994;
18(4): 60-74.
16. United States Pharmacopoeia and the National
Formulary XXIII, 18th ed,. Rockville, MD: The
United States Pharmacopoeia Convention Inc.,
1995, pp 1982 – 1984.
17. Chapman GM, Amer G, Boyce C, Brower G, Green
C, Hall WE, Harpaz D, Mullendore B. Proposed
Validation Standard VS1: Non-aseptic
Pharmaceutical Processes. J Val Technol 2000;
6:502-20.
18. LeBlane DA. Establishing scientifically justified
acceptance criteria for cleaning validation of
finished drug product. Pharm Technol 1998;
23(10): 136-48.
19. WHO Expert Committee on Specifications for
Pharmaceutical Preparations, 34th Report. WHO
Technical Report Series no. 863, Annex 6,
Geneva: WHO, 1966, pp 80-96.
20. WHO Expert Committee on Specifications for
Pharmaceutical Preparations, 32nd Report. WHO
Technical Report Series no. 823 Annex 5.
Geneva: WHO, 1992, pp.117-21.
21. Guideline on General Principles of Process
Validation. Washington DC: Center for Drug
Evaluation and Research, US Food and Drug
Administration, May 1987, p 9.
22. Good Manufacturing Practices for Pharmaceutical
Products, WHO/Pharm./93.562/Annex: Guidelines
on Validation of Manufacturing Process.
Geneva: WHO.
23. Nash RA. Process Validation of a 17-Year
retrospective study of solid dosage forms. Drug
Dev Ind Pharm 1966; 22 (1): 25-34.
24. Good Manufacturing Practices for Pharmaceutical
Products. WHO Expert Committee on
Specifications for Pharmaceutical Preparations.
32nd Report, WHO Technical Report Series no.
823. Geneva: WHO, 1992: pp 14-96.

Cleaning Validation

Table of contents
1. Foreword....................................................................................................…..... 2
2. Objective....................................................................................................…..... 3
3. Scope..……................................................................................................…..... 4
4. Potential residues …………………………….................................................. 5
5. Current regulatory guidance……………….................................................... 6
6. Cleaning validation policy........................................................................…..... 7
7. Levels of cleaning.………….....................................................................…..... 8
8. Elements of cleaning validation...............................................................…..... 10
8.1 Establishment of acceptance criteria….................................................... 12
8.1.1 chemical determination ........................................................................ 12
8.1.2 physical determination ......................................................................... 13
8.1.3 microbiological determination.............................................................. 13
8.2 Cleaning procedures ............................................................................... 13
8.3 Sampling ................................................................................................ 15
8.4 Analytical methods…. ............................................................................ 16
8.5 Validation protocols ............................................................................... 17
8.6 Validation reports................................................................................... 18
9. Minimum requirements...........…..............................................................…..... 20
10. Change control…………..........…..............................................................…..... 21
11. Summary………………...........…..............................................................…..... 22
12. References…………..…...........…..............................................................…..... 23
Guide to Cleaning Validation in API plants
2
1. Foreword
This Guideline has been produced by the Active Pharmaceutical Ingredients Committee
(APIC) Working group.
Different organizations will be influenced by their companies and the markets that they
serve in the approaches that they take and the policies that they have with respect to
the subject.
It is also valuable to bear in mind that this is an area that is changing rapidly and what
was considered as being acceptable 2-5 years ago is now not adequate. Therefore,
companies should be aware of the need to continuously update themselves on current
regulatory requirements.
Guide to Cleaning Validation in API plants
3
2. Objective
The intention of this document has been to define a comprehensive approach to the
Validation of Cleaning procedures in Active Pharmaceutical Ingredient manufacturing
facilities.
Cleaning Validation in the context of Active Pharmaceutical Ingredient manufacture
may be defined as:
The process of providing documented evidence that the cleaning methods
employed within a facility consistently controls potential carryover of product
(including intermediates and impurities), cleaning agents and extraneous
material into subsequent product to a level which is below predetermined levels.
It is necessary to Validate Cleaning procedures for the following reasons:
a. It is a customer requirement - it ensures the safety and purity of the product.
b. It is a regulatory requirement in Active Pharmaceutical Ingredient product
manufacture.
c. It also assures from an internal control and compliance point of view the quality
of the process.
Guide to Cleaning Validation in API plants
4
3. Scope
This Document will serve to:
1. Define the basic concepts and terms associated with Cleaning Validation in the
Active Pharmaceutical Ingredient industry.
2. Serve as a guide from which Masterplans, Protocols and Reports may be
compiled.
Note: General validation principles and a glossary of terms also relevant to cleaning
validation are detailed in the CEFIC / EFPIA Guide entitled ‘Good Manufacturing
Practices for Active Pharmaceutical Ingredient Manufacturers’.
It applies to sterile API’s only up to the point where the API is rendered sterile.
Guide to Cleaning Validation in API plants
5
4. Potential residues
The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of
Active Pharmaceutical Ingredients by both chemical and physical means through a
series of multiple step processes. Plants or individual pieces of equipment, including
ancillary equipment, may be used in multi-product manufacture or dedicated to
individual products.
The result of inadequate cleaning procedures is that any of a number of contaminants
may be present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient
2. By-products and/or degradation products of the Active Pharmaceutical
Ingredient
3. The previous product
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms
This is particularly the case where microbial growth may be sustained by the
product.
6. Cleaning agents themselves and lubricants
Guide to Cleaning Validation in API plants
6
5. Current regulatory guidance
Refer to the reference section of this document for details of current Regulatory
Guidance.
Guide to Cleaning Validation in API plants
7
6. Cleaning validation policy
The main focus of this document will be to describe equipment and ancillary equipment
/ process Cleaning Validation in an Active Pharmaceutical Ingredient manufacturing
plant. However, it is appropriate to start by giving a brief introduction as to how the
concept of Cleaning Validation should be approached in a facility.
It is advisable for Active Pharmaceutical Ingredient manufacturing facilities to hold an
official Cleaning Validation Policy. Specific department responsibilities should be
outlined in this and it should be approved by senior management. This policy should
serve to provide a general guideline and direction for company personnel, regulatory
authorities and customers as to how the company deals with areas associated with
Cleaning Validation.
The policy should incorporate the following types of statements:
· Definition of terms employed during validation i.e. rinse vs. flush vs. wash etc.
· A statement specifying what company policy is on validation of cleaning
procedures related to equipment (including ancillary) and processes.
· Company policy re dedication of equipment in certain cases (if products are
deemed too dangerous and / or highly active to manufacture on multi-product
equipment).
· Analytical validation policy.
· The policy should also state the rational for the methods by which acceptance
criteria is determined.
· Revalidation policy.
Guide to Cleaning Validation in API plants
8
7. Levels of cleaning
The degree or level of cleaning and validation required for processes in Active
Pharmaceutical Ingredient manufacturing depends largely on:
· The equipment usage (i.e. dedicated equipment or not)
· The stage of manufacture (early, intermediate or final step)
· The nature of the potential contaminants (toxicity, solubility etc.)
Each of the above three bullets must be evaluated based on the next product, not
only toxicology etc. The rational for this statement is given below:
In general, the higher the potential for finished Active Pharmaceutical Ingredient
contamination the greater the requirement to validate cleaning methods to ensure
product safety.
Active Pharmaceutical Ingredient manufacturers may have different levels of cleaning
requirements in facilities based on the stage of the process being cleaned and the
subsequent product to be manufactured.
Table 1 on page 7 illustrates an example of how a company may decide on the level of
cleaning between lots.
It is the responsibility of the manufacturer to demonstrate that the level of cleaning and
validation performed is adequate based on each individual situation and on a justifiable
scientific rational.
Cleaning should be carried out as soon as practical after the end of processing and
should leave the plant in a suitable condition for next use.
Guide to Cleaning Validation in API plants
9
Table 1: levels of cleaning
LEVEL USED WHEN CLEANING
VALIDATION REQUIRED
LEVEL 2 i.e.
· Product changeover of
equipment used in final
step
· Intermediates of one
batch to final step of
another
yes – essential
LEVEL 1 i.e.
· Intermediates or final
Step of one product to
intermediate of another
· Early Step to
intermediates in a
product sequence
progression between level
0 and 2 depending on
process and nature of
contaminant based on
scientific rational
LEVEL 0 i.e. in-campaign, batch to
batch changeover
no validation required
NB: ALL PROCESSES MUST BE EVALUATED INDIVIDUALLY
Guide to Cleaning Validation in API plants
10
8. Elements of cleaning validation
A brief outline of the various elements of a basic cleaning validation study is given
below (see also Figure 1 on page 11).
This is followed by a more detailed view of the individual elements in this section.
I. Establishment of acceptance criteria
II. Cleaning procedure
· Identification of the equipment
· characterization of the products (Previous: activity/toxicity,
solubility, subsequent: dosage, lot size)
· determination and characterization of the cleaning agents
III. Analytical method and its validation
IV. Sampling Procedure and necessary validation of same
V. Validation protocol
VI. Validation report
Guide to Cleaning Validation in API plants
11
EVALUATE EQUIPMENT SURFACES
AND DETERMINE
1. Worst case locations to sample (swab
sampling)
1. Volume and type of rinse solvent to be
employed (rinse sampling)
1. Equipment surface area (necessary to
calculate carryover into subsequent
batches)
DETERMINE THE MOST APPROPRIATE CLEANING
PROCEDURE FOR THE EQUIPMENT -
1. Generate acceptance criteria data for the contaminant.
2. The cleaning method will be determined by the process,
the equipment the cleaning agents and the cleaning
techniques available.
3. All aspects of the cleaning procedure should be clearly
defined in SOPs be they manual / CIP or COP
DEVELOP AND VALIDATE THE
SAMPLING AND CHOSEN
ANALYTICAL METHODS
FOR THE COMPOUND(S) BEING
CLEANED
1. Swab
2. Rinse
(determine % recovery, limit of detection,
limit of quantitation, accuracy of method,
reproducibility, stability over time ...etc.)
INTERIM REPORT:
GENERATE INTERIM CLEANING
VALIDATION REPORTS ON A CLEAN BY
CLEAN BASIS DETAILING THE
ACCEPTABILITY OF THE CLEANING
PROCEDURE FOR THE EQUIPMENT AND
THE PRODUCT.
This is only required where there is a long
period of time between manufacture of the
validation runs (see stage 4 for reporting
requirements).
Figure 1: Cleaning Validation Process
STAGE 1:
STAGE 2: STAGE 3 STAGE 4:
DEVELOP A CLEANING VALIDATION PROTOCOL
FOR THE PRODUCT AND THE EQUIPMENT BEING
CLEANED
That should encompass for example:
1. Introduction
2. Scope
3. Equipment
4. Cleaning procedure
5. Sampling procedures
6. Analytical testing procedure
7. Acceptance/Cleaning limits.
8. Acceptance criteria for the validation.
GENERATE A CLEANING VALIDATION
REPORT DETAILING THE ACCEPTABILITY
OF THE CLEANING PROCEDURE FOR THE
EQUIPMENT AND THE PRODUCT
The report should give a full detailed background and
introduction to the cleaning Validation study and
should evaluate all data generated with respect to the
acceptance criteria employed for the study. The report
should also indicate the requirement if any for
revalidation (period of time /change control etc.)
Guide to Cleaning Validation in API plants
12
8.1 Establishment of acceptance criteria
The Cleaning Validation should demonstrate that the procedure consistently
removes residues of the substance previously manufactured down to levels that
are acceptable and that the cleaning procedure itself does not contribute
unacceptable levels of residual materials to the equipment. The limits set
should be practical, achievable and justifiable.
In Active Pharmaceutical Ingredient manufacture there may be partial reactants
and unwanted by-products which may not have been chemically identified.
Therefore, it may be necessary to focus on by-products as well as the principle
reactant. Companies should decide on which residue(s) to quantify based on
sound scientific rational.
8.1.1 Chemical determination
It is generally the residual Active Pharmaceutical Ingredient or intermediate,
which is of greatest concern rather than reaction side products or residual
impurities.
There are a number of options available when determining acceptance criteria.
Where either toxicological or therapeutic data if available then calculation A or
B is preferable. If data is not available for either of these calculations or if the
result is more stringent calculation C should be used.
A. Limiting the level based on toxicity data.
An Acceptable Daily Intake (ADI) is calculated with suitable safety
factors applied and this is converted to the maximum allowable
carryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in each piece
of equipment, such that no greater than 1/1000 of the normal
therapeutic dose will be present per typical dose of the next product to
be run in the equipment. The validation protocol should include a
calculation, which ties this philosophy to the acceptance criteria for the
samples to be tested.
C. Limiting the level of product which could appear in the following
products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5% total
unknowns material may be present in the product being tested )
Note FDA Statement on 0.1% impurities
Guide to Cleaning Validation in API plants
13
FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise,
June 98: „...we have found that some firms have incorrectly applied as
their acceptance limit the 0.1% impurity identification threshold as
discussed in both the ICH impurity guideline and the U.S.P. General
Notices. This application of the 0.1% impurity threshold is
inappropriate because the limit is intended for qualifying impurities that
are associated with the manufacturing process of related compound and
not extraneous impurities caused by cross contamination. ...“ ) may be
used depending on the stage of the process.
It is also necessary to evaluate the ability of the cleaning procedure to
remove any cleaning agents introduced. The acceptance criteria for the
residual-cleaning agents should reflect the absence of these materials,
within the range of the capabilities of the assay and sampling methods.
The individual company must decide on the Acceptance Criteria which
are justifiable for their particular situation.
8.1.2 Physical determination
There should be provision during routine cleaning for a visual examination of
the equipment, verifying that it is free of visible residues. The validation
protocol should include this requirement as an acceptance criteria. During
validation, special attention should be given to areas that are ‘hard to clean’
(e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would
be difficult to verify on a routine basis.
8.1.3 Microbiological determination
Appropriate studies should be performed (e.g. swabs and/or rinse sampling)
where the possibility of microbial contamination of subsequent product is
deemed possible and presents a product quality risk.
8.2 Cleaning procedures
Written cleaning procedures for each piece of equipment and process1 must be
prepared. It is vital that the equipment design is evaluated in detail in
conjunction with the product residues to be removed, the available cleaning
agents and cleaning techniques when determining the optimum cleaning
procedure for the equipment.
1 If one cleaning procedure has been shown to be adequate for a number of products, then it is only
necessary to have one cleaning SOP for those products for each piece of equipment.
Guide to Cleaning Validation in API plants
14
Cleaning procedures should be sufficiently detailed to remove the possibility of
any inconsistencies during the cleaning process.
A. Equipment parameters to be evaluated
· Identification of the equipment to be cleaned
· Difficult to clean areas
· Property of materials
· Ease of disassembly
· Fixed or not
· Etc.
B. Residues to be cleaned
· Cleaning limits
· Solubility's of the residues
· Length of campaigns
· Etc.
C. Cleaning agent parameters to be evaluated
· Preferably materials that are normally used in the process
· Detergents available (as a general guide, minimize use of detergents unless
absolutely required)
· Solubility properties
· Environmental considerations.
· Health and safety considerations
· Etc.
D. Cleaning techniques to be evaluated
· Manual cleaning
· CIP (Clean-in place)
· COP (clean-out-of-place)
· Semi automatic
· Automatic
· Time considerations
· Number of cleaning cycles
· Etc.
E. Other requirements
Guide to Cleaning Validation in API plants
15
Procedures must be determined to be operator independent i.e. rugged and
reproducible, during the validation studies.
The Cleaning documentation should include the following items in order to ensure that
it can be followed reproducibly and maintained subsequent to Validation.
· Detailed definition of levels of cleaning to be performed.
· Detailed description of cleaning methods.
· The necessity to inspect and verify equipment cleanliness prior to manufacture of
next batch should be stated in the SOP and recorded on the batch record.
· The SOP should detail where verification of cycle parameters (if automated) and
checklists (for complex manual procedures) is necessary.
· Where microbial contamination may be an issue, consideration should be given to
the integrity of the vessel prior to manufacture.
Written cleaning procedures may also include additional items not specified above,
these would include, as an example, the steps needed to protect the equipment from
contamination after cleaning.
8.3 Sampling
In developing the sampling plan for a validation study, it makes scientific sense
to
incorporate an understanding of the acceptance criteria and the limitations of the
sampling method relative to the surface to be sampled.
The two methods of sampling generally employed are swab and / or rinse
sampling. (If neither or these methods is shown be a scientifically sound method
for testing in a specific instance then an alternative is to consider testing the next
product.)
The selection of either of these techniques must be consistent with sound
scientific judgment and must support the objective of the study, which is to
demonstrate that the amount of residual material in the equipment has been
reduced to acceptable levels.
Each method is described in brief below.
1. SWAB:
· Swab sampling does not cover the entire equipment surface area therefore
sites must be chosen with care. It is important that, as a minimum, the
Guide to Cleaning Validation in API plants
16
swab sites represent worst case locations on the equipment and that the
result is then extrapolated to account for the total product contact surface
area. This calculation makes it possible to make a worst case determination
of potential carryover into subsequent product.
· Due to the nature of this method which employs physical forces as well as
chemical forces it may be necessary to perform sampling technique
evaluation.
· Swabbing efficiency (% recovery) for the swabbing method must be
determined.
· It is necessary to ensure that extractables of the swab do not interfere with
the sampling method.
· Using this technique it is possible to sample insoluble residues due to the
physical action associated it.
2. RINSE:
· The solvent rinse occurs after cleaning has been completed
· This method is not as direct as swabbing but will cover the entire surface
area (and parts inaccessible to swabs)
· It is important to ensure chosen solvent has appropriate recovery for
residues being quantified
· This method allows much greater ease of sampling than swabbing
· A reduced no of samples are required to generate a carryover figure.
(Other sampling methods which may be employed in addition to swab / rinse
sampling during a validation may include: placebo sampling, testing subsequent
batches for residues, use of coupons (test pieces), etc. )
8.4 Analytical methods
In order for the analytical testing of the cleaning validation samples (swabs or
rinses) to yield meaningful results, the analytical methods used should be
validated. This should be documented.
The basic requirements are:
· The ability to detect the target substance(s) at levels consistent with the
acceptance criteria
· The ability to detect the target substance(s) in the presence of other
materials that may also be present in the sample (selectivity)
(Companies might want to consider the following:
Guide to Cleaning Validation in API plants
17
Where more than one impurity is suspected (which is probably the normal
case in API manufacturing) a method could be proposed that is not
necessarily specific for each of the impurities but detects them all
together. Then additionally the assumption must be made, that the worst
case (e.g. most active) impurity represents the whole residue. This is
secure approach for the patients and could be accepted by the authorities.
It is also an practicable approach for the industry because such methods
are for example dry residue determination for non volatile impurities or
TOC determination for water rinses, which are very simple methods. )
· The analytical method should include a calculation to convert the amount
of residue detected in the sample to 100% if the recovery data generated
indicates a recovery outside of an allowed range.
· Stability of samples over time if the time interval between removal and
testing of samples potentially effects sample integrity.
8.5 Validation protocols
A Validation Protocol is necessary to define the specific items and activities
that will constitute a cleaning validation study. It is advisable for companies to
have drawn up a Master Validation plan indicating the overall Cleaning
Validation strategy for either the product range / equipment type / entire site.
The protocol must be prepared prior to the initiation of the study and must
either include or reference the documentation required to provide the following
information:
· The objective of the study:
What cleaning process is to be validated (indicating the product to be
removed and the equipment from which it is to be removed)?
If this study is to be employed to demonstrate the acceptability of the
cleaning procedure for a group of products the rational for doing so
should also be detailed here.
The cleaning procedure(s) to be validated should be identified i.e.
cleaning agents, soakage times, equipment parameters, number of
cleaning cycles etc.
Guide to Cleaning Validation in API plants
18
· Scope of the study:
The company must evaluate the process and determine which residues are
to be tested for and which are not to be based on sound scientific
rational.
What residues (including cleaning agents) are to be tested for, why those
residues (if more residues may be present than are being tested for all
residues should be under control see comments at 8.4). How many times
should the study be run before a report is compiled and recommendations
made.
· Listing of the process parameters to be verified
This is particularly necessary when automated or semi-automated
cleaning techniques are to be employed.
· Sampling and inspection procedure to be used.
The types of sampling methods to be used, where the samples are to be
removed from and how many samples are to be taken. Any particular
requirements should also be stated i.e. for sterile sampling / sampling
light sensitive products.
An equipment sampling diagram should be referenced.
· Personnel responsibilities during the study
· Test methods to be used (should be referenced): See Section 8.4.
· Acceptance criteria
Physical: see section 8.1.2
Chemical: see section 8.1.1
(The rational for this criterion should be given along with a calculation
step.)
· Change control: See section 10.
· Approval of protocol before the study.
Guide to Cleaning Validation in API plants
19
8.6 Validation reports
A validation report is necessary to present the results and conclusions and
secure approval of the study. The report should include the following:
· Summary of or reference to the procedures used to clean, sample and test
· Physical and analytical test results or references for same, as well as any
pertinent observations
· Conclusions regarding the acceptability of the results, and the status of
the procedure(s) being validated
· Any recommendations based on the results or relevant information
obtained during the study including revalidation practices if applicable.
· Approval of conclusions
· Review any deviations for the protocol that occurred.
· In cases where it is unlikely that further batches of the product will be
manufactured for a period of time it is advisable to generate interim
reports on a batch by batch basis until such time as the cleaning validation
study has been completed. (Typically, in Active Pharmaceutical
Ingredient Pharmaceutical manufacture, verification is deemed
appropriate during development of the cleaning methods. Where
products are manufactured infrequently, verification may be applied over
a period of time until all measuring data has been collected for the
Validation Report.)
· The report should conclude an appropriate level of verification
subsequent to validation.
Guide to Cleaning Validation in API plants
20
9. Minimum requirements
If company policy is not to validate all equipment cleaning procedures for all products
then as a minimum requirement the validation policy should encompass conditions
which represent the most appropriate challenges (worst case) to the procedure.
These would include, as an example, such things as:
· Removal of products which contain the products with the greatest biological
activity.
· Removal of products containing the products/intermediates/byproducts with the
least solubility.
These represent studies that are minimally required as part of a validation, the results
from which could be used to support lesser challenges to the procedure. It is often
termed product grouping.
· The maximum idle time before cleaning.
A validation program generally encompasses three consecutive successful replicates to
establish that the procedure is reproducibly effective although companies should
evaluate each situation individually.
Where equipment of similar size, design and construction is cleaned by the same
procedure, studies need not be conducted on each unit, as long as a total of three
successful replicates are done on similar pieces of equipment (equipment grouping).
Concurrent Validation may be appropriate when product is manufactured infrequently.
Guide to Cleaning Validation in API plants
21
10. Change control
Validated cleaning procedures should be included in the change control program. This
will ensure that any proposed changes are evaluated fully for their impact on the
validated state of the procedure. Where deemed necessary, the proposed revised
procedure may need to be validated prior to routine implementation.
Cf. Change control chapter in the CEFIC / EFPIA Guide entitled ‘Good
Manufacturing Practices for Active Ingredient Manufacturers’
In the absence of an intentional change to a procedure, it is reasonable to assume that
properly trained operators or a properly qualified automated system will be able to
execute the procedure reproducibly and obtain the desired outcome - reduction of
residue to acceptable levels. There may exist special circumstances that would suggest
that this assumption be verified via testing. This may be addressed by periodic reviews
or re-evaluations.
Guide to Cleaning Validation in API plants
22
11. Summary
A validation policy should be written for a plant including cleaning validation.
An cleaning validation program should contain the following elements:
1. Assess equipment and products (previous, following)
2. Assess impact of this process on routine processes. If covered under bracketing
then no further validation is required.
3. Determine an appropriate cleaning agent and method
4. Determine acceptance criteria for the residue(s) (including cleaning agents).
5. Determine degree of evaluation required to validate the procedure.
6. Decide what residue(s) (including cleaning agents), are to be tested for based on
solubilities, toxicities etc. and document rational behind decision.
7. Develop sampling and analytical methods for recovery and detection of residues
(swab/rinse, HPLC/dry residue etc.)
8. Acceptance Criteria for the Validation
9. Compile and approve Validation protocol
10. Perform Validation Studies in accordance with protocol
11. Compile and approve a Validation report documenting studies, conclusions and
recommendations.
12. Revalidation policy
Guide to Cleaning Validation in API plants
23
12. References
ICH:
· ICH Good Manufacturing Practice Guideline for Active Pharmaceutical
Ingredients. (July 23 1999)
PIC :
· Principles of Qualification and Validation in Pharmaceutical Manufacture -
Recommendations on Cleaning Validation. (ref. Document PR 1/ 99 March
1999)
FDA:
· Guide to inspections of validation of cleaning processes (July 1993)
· Biotechnology inspection guide (1991)
· Foreign inspection guide (1992)
· Guide to inspection of bulk pharmaceutical chemicals
· Guide to inspections of topical drug products
· Manufacture, processing or holding of active pharmaceutical ingredients, draft
document, FDA, March 1998.
CEFIC / EFPIA:
· Good Manufacturing Practices for Active Ingredient Manufacturers - August
1996.
PHRMA :
· Draft PhRMA BPC Cleaning Validation Guideline. (November 1996 Edition)
OTHER PUBLICATIONS
· S.W. Harder, ‘The validation of cleaning processes’, pharmaceutical technology.
(1984)
· James Agalloco, ‘Points to consider in the validation of equipment cleaning
procedures’, Journal of parenteral science and technology. (October 1992)
Guide to Cleaning Validation in API plants
24
· Fourman Mullen, ‘Determining cleaning validation acceptance limits for
pharmaceutical manufacturing operations’, pharmaceutical technology. (April
1993)
· Mc Cormick, Cullen, ‘Cleaning validation’, pharmaceutical process validation,
second edition. (1992)
· Mc Arthur, Vasilevsky, ‘Cleaning validation for biological products: case study’,
pharmaceutical engineering. (November / December 1995)
· Zeller, ’Cleaning Validation and residue limits: a contribution to current
discussions’, pharmaceutical technology Europe. (November 1993)

An Essentiality In The Pharmacy

Tarun Virmani

The development of a drug product is a lengthy process involving drug discovery, laboratory testing, animal studies, clinical trials and regulatory registration.

To further enhance the effectiveness and safety of the drug product after approval, many regulatory agencies such as the United States Food and Drug Administration (FDA) also require that the drug product be tested for its identity, strength, quality, purity and stability before it can be released for use. For this reason, pharmaceutical validation and process controls are important in spite of the problems that may be encountered¹. Process controls include raw materials inspection, in-process controls and targets for final product. The purpose is to monitor the on-line and off-line performance of the manufacturing process and then validate it. Even after the manufacturing process is validated, current good manufacturing practice also requires that a well written procedure for process controls is established to monitor its performance². This paper provides an overview of pharmaceutical validation and process controls in drug development. The validation concept can be applied to new drugs, new dosage forms and generic drug development.

Essentials of Pharmaceutical Validation

Validation is an integral part of quality assurance; it involves the systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. A validated process is one which has been demonstrated to provide a high degree of assurance that uniform batches will be produced that meet the required specifications and has therefore been formally approved. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control³. Adequate validation is beneficial to the manufacturer in many ways:

• It deepens the understanding of processes; decreases the risk of preventing problems and thus assures the smooth running of the process.
• It decreases the risk of defect costs.

• It decreases the risk of regulatory noncompliance.
• A fully validated process may require less in-process controls and end product testing.

Validation should thus be considered in the following situations:

• Totally new process
• New equipment
• Process and equipment which have been altered to suit changing priorities and
• Process where the end-product test is poor and an unreliable indicator of product quality.

When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process should be shown to yield a product consistent with the required quality. In this phase, the extent to which deviations from chosen parameters can influence product quality should also be evaluated. When certain processes or products have been validated during the development stage, it is not always necessary to revalidate the whole process or product if similar equipment is used or similar products have been produced, provided that the final product conforms to the in-process controls and final product specification. There should be a clear distinction between in-process control and validation. In production, tests are performed each time on a batch to batch basis using specifications and methods devised during the development phase. The objective is to monitor the process continuously⁴.

Major Phases in Validation

The activities relating to validation studies may be classified into three:

Phase 1:

This is the Pre-validation Qualification Phase which covers all activities relating to product research and development, formulation pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions and storage, and handling of in-process and finished dosage forms, equipment qualification, installation qualification, master production document, operational qualification and process capacity.

Phase 2:

This is the Process Validation Phase. It is designed to verify that all established limits of the critical process parameter are valid and that satisfactory products can be produced even under the worst conditions.

Phase 3:

Known as the Validation Maintenance Phase, it requires frequent review of all process related documents, including validation of audit reports, to assure that there have been no changes, deviations, failures and modifications to the production process and that all standard operating procedures (SOPs), including change control procedures, have been followed. At this stage, the validation team comprising of individuals representing all major departments also assures that there have been no changes/deviations that should have resulted in requalification and revalidation. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications. It is assumed that throughout manufacturing and control, operations are conducted in accordance with the principle of good manufacturing practice (GMP) both in general and in specific reference to sterile product manufacture⁵. The validation steps recommended in GMP guidelines can be summarized as follows:

• As a pre-requisite, all studies should be conducted in accordance with a detailed, pre-established protocol or series of protocols, which in turn is subject to formal – change control procedures.

• Both the personnel conducting the studies and those running the process being studied should be appropriately trained and qualified and be suitable and competent to perform the task assigned to them.

• All data generated during the course of studies should be formally reviewed and certified as evaluated against pre-determined criteria.

• Suitable testing facilities, equipment, instruments and methodology should be available.

• Suitable clean room facilities should be available in both the ‘local’ and background environment. There should be assurance that the clean room environment as specified is secured through initial commissioning (qualification) and subsequently through the implementation of a programme of re-testing – in-process equipment should be properly installed, qualified and maintained.

• When appropriate attention has been paid to the above, the process, if aseptic, may be validated by means of “process simulation” studies.

• The process should be revalidated at intervals and

• Comprehensive documentation should be available to define support and record the overall validation process⁶.

Process Validation

Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality⁵. It would normally be expected that process validation be completed prior to the release of the finished product for sale (prospective validation). Where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes, which have been in use for some time without any significant changes, may also be validated according to an approved protocol (retrospective validation) ^6-13.

Pre-requisites for Process Validation

Before process validation can be started, manufacturing equipment and control instruments as well as the formulation must be qualified. The information on a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before an application for marketing authorization is submitted. This involves studies on the compatibility of active ingredients and recipients, and of final drug product and packaging materials, stability studies, etc. Other aspects of manufacture must be validated including critical services (water, air, nitrogen, power supply, etc.) and supporting operations such as equipment cleaning and sanitation of premises. Proper
training and motivation of personnel are prerequisites to successful validation^14-16.

Process validation decision

The following model may be useful in determining whether or not a process should be validated:

Figure 1 - Process validation decision tree
The model shown describes a decision tree that a manufacturer can follow when deciding on whether a process needs to be validated. The process under consideration in this model is the simplest possible - many processes may be large and/or a complex set of sub-processes.
Each process should have a specification describing both the process parameters and the output desired. The manufacturer should consider whether the output can be verified by subsequent monitoring or measurement (A). If the answer is positive, then the consideration should be made as to whether or not verification alone is sufficient to eliminate unacceptable risk and is a cost effective solution (B). If yes, the output should be verified and the process should be appropriately controlled (C). If the output of the process is not verifiable then the decision should be to validate the process (D); alternatively, it may become apparent that the product or process should be redesigned to reduce variation and improve the product or process (E). Also, a change in a manufacturing process may result in the need for process validation even though the process formerly only required verification and control. The risk or cost may also be reduced by redesigning the product or process to a point where simple verification is an acceptable decision (E).

The Pharmaceutical Process Equipment

The key idea of validation is to provide a high level of documented evidence that the equipment and the process conform to a written standard. The level (or depth) is dictated by the complexity of the system or equipment. The validation package must provide the necessary information and test procedures required to provide that the system and process meet specified requirements. Validation of pharmaceutical process equipment involves the following:

• Installation Qualification

This ensures that all major processing and packaging equipment, and ancillary systems are in conformity with installation specification, equipment manuals schematics and engineering drawing. It verifies that the equipment has been installed in accordance with manufacturers recommendation in a proper manner and placed in an environment suitable for its intended purpose.

• Operational Qualification

This is done to provide a high degree of assurance that the equipment functions as intended. Operational qualification should be conducted in two stages:

•  
  1. Component Operational Qualification, of which calibration can be considered a large part.

•  
  1. System Operational Qualification to determine if the entire system operates as an integrated whole.

• Process Performance Qualification

This verifies that the system is repeatable and is consistently producing a quality product. These exercises assure, through appropriate performance lists and related documentation, that equipment, ancillary systems and sub-systems have been commissioned correctly. The end results are that all future operations will be reliable and within prescribed operational limits. At various stages in a validation exercise there are needs for protocols, documentation, procedures, specifications and acceptance criteria for test results. All these need to be reviewed, checked and authorized. It would be expected that representatives from the professional disciplines, e.g., engineering, research and development, manufacturing, quality control and quality assurance are actively involved in these undertakings with the final authorization given by a validation team or the quality assurance representative¹⁷.

Conclusion:

It is necessary, before approval of a new drug, that an accurate and reliable assessment for its effectiveness and safety for the intended indication and target patient population is demonstrated. Pharmaceutical validation which includes assay validation, cleaning validation, equipment validation as well as the overall process validation is crucial in stability analysis, animal studies and early phases of clinical development such as bioavailability/bioequivalence studies. After the drug is approved, pharmaceutical validation and process control are necessary to ensure that the drug product will meet/set pharmaceutical standards for identity, strength, quality, purity, stability, evaluation safety and efficacy. In general, pharmaceutical validation and process control provide a certain assurance of batch uniformity and integrity of the product manufactured.

References:

1. Sharp JR. The Problems of Process Validation. Pharm J 1986; 1:43-5.
2. Chow S. Pharmaceutical Validation and Process Controls in Drug Development. Drug Inf J 1997; 31: 1195-201.
3. Committee on Specifications for Pharmaceutical Preparations. Good Manufacturing Practices for Pharmaceutical Products. WHO Technical Report Series no. 82. Geneva: World Health Organization, 1992, pp 14-79.
4. South African Guide to Good Manufacturing Practice. Pretoria: Medicines Control Council, 1996. http://www.pharmanet.co.za/mcc /inpectorate/ins-71998.htm .
5. Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issued for Development and Validation. WashingtonDC: US Food and Drug Administration, 1994.
6. Therapeutics Products Programme. Process Validation: Aseptic Processes for Pharmaceuticals. http://www.hc-sc.gc.ca/hpbdgps/ therapeutic; downloaded March 30, 2001.
7. Rosendale DM. Process Equipment 1990. www.vectorcorporation.com/download/val_in terphex.
8. Cleaning Validation in Active Pharmaceutical Ingredient Manufacturing Plants. Brussels: Active Pharmaceutical Ingredients Committee. http://www.apic.cefic.org/pub4cleaningval/1999pdf; downloaded September 1999.
9. Guide to Inspections Validation of Cleaning Processes. WashingtonDC: US Food and Drug Administration. http://www.fda.gov/ora/inspect _ref/igs/valid.html.
10. Cleaning Validation Guidelines. Ottawa, Canada: Health Products and Food Branch Inspectorate, Health Canada, May 2000, p 11.
11. Harder SW. The Validation of Cleaning Procedures. Pharm Technol 1984; 8(5): 29-34.
12. Jenkins KM, Vanderwielen AJ. Cleaning Validation: An Overall Perspective. Pharm Technol 1994; 18(4): 60-74.
13. United States Pharmacopoeia and the National Formulary XXIII, 18th ed,. Rockville, MD: The United States Pharmacopoeia Convention Inc., 1995, pp 1982 – 1984.
14. Chapman GM, Amer G, Boyce C, Brower G, Green C, Hall WE, Harpaz D, Mullendore B. Proposed Validation Standard VS1: Non-aseptic Pharmaceutical Processes. J Val Technol 2000; 6:502-20.
15. LeBlane DA. Establishing scientifically justified acceptance criteria for cleaning validation of finished drug product. Pharm Technol 1998; 23(10): 136-48.
16. WHO Expert Committee on Specifications for Pharmaceutical Preparations, 34th Report. WHO Technical Report Series no. 863, Annex 6, Geneva: WHO, 1966, pp 80-96.
17. Good Manufacturing Practices for Pharmaceutical Products, WHO/Pharm./93.562/Annex: Guidelines on Validation of Manufacturing Process. Geneva: WHO.

Sterilization Process Validation

Sterilization Process Validation
Title: Sterilization Process Validation
Manual Number: 039
Prepared by: Date: Supersedes:
Checked by: Date: Date Issued:
Approved by: Date: Review Date:
5
4 Responsibilities
All sterile manufacturing sites or its contractors are responsible for ensuring that
sterilization processes used to produce items are properly validated.
5 Guideline
Validation of processes used to sterilize drug products and equipment are the most critical
validation activities undertaken. Common elements in the validation of any sterilization
process include:
􀂇 Sterilization Cycle Development
􀂇 Biological and Physical Measurement Controls
􀂇 Empty Chamber Studies
􀂇 Loaded Chamber Studies
􀂇 Routine Use/Ongoing Monitoring
􀂇 Validation Maintenance/Change Control/Revalidation
The sterilization method chosen depends on the application. The following methods are
typically available:
Method Typical application
Steam
sterilization
For the sterilization of fluids in ampoules, vials etc, or the
sterilization of processing equipment, reactors, preparation
tanks, solution delivery piping, etc. In general, sterilization
through the application of saturated steam under pressure is the
preferred method of sterilization. The principles apply to SIP
processes as well.
Sterilization by
filtration
Used for those products that cannot be sterilized due to the
heat sensitivity of the product or where heat labile packaging
is chosen since it provides a distinct patient benefit. Not the
preferred sterilization method.
Dry heat
sterilization and
Depyrogenation
Used to sterilize/depyrogenate containers (ampoules, vials,
etc.), pharmaceutical raw materials and processing equipment.
The use of dry heat has little application for the sterilization of
pharmaceutical drug products.
Radiation
sterilization
To sterilize packaging equipment, consumables, garments etc.
that are difficult to sterilize using steam or other methods.
Radiation sterilization is mostly used for medical devices.
5.1 Steam Sterilization
Steam Sterilization is the most common type of sterilization employed in the
pharmaceutical manufacturing environment. The principles of steam sterilization
are applicable to processes conducted within autoclaves as well as sterilizationin-
place (SIP) processes.
For the sterilization of fluids in e.g. vials and ampoules, a fluids load autoclave
cycle is used. The steam (or superheated water) is used as a heat transfer medium
to heat the contents of the vials/ampoules. The moisture required for sterilization
is derived from the contents in the vial/ampoule.
9
minute of the exposure stage.
The difference between the control probe, recording chart probe and independent
sensor (usually a thermocouple) during the exposure stage should not exceed + 1.0􀂃C.
5.1.1.2 Loaded Chamber Temperature Distribution
This study must be included to demonstrate that the equipment loading
patterns do not significantly change the chamber temperature distribution
within the chamber. Typically thermocouples are distributed throughout the
chamber (not in contact with load items) as for the Empty Chamber Temperature
Distribution study and cycles may be run using both the maximum and minimum
loads.
Loaded Chamber Temperature Distribution studies should meet an acceptance
criteria for the temperature to be within + 1􀂃C of the mean loaded chamber
temperature after one minute of the exposure stage.
The difference between the control probe, recording chart probe and independent
sensor during the exposure stage should not exceed + 1.0􀂃C.
5.1.1.3 Heat Penetration Studies
Loaded chamber heat penetration studies must be performed to demonstrate
that the pre-required time at temperature criteria are met for the loads being
validated. The heat penetration locations to be monitored are assessed
using both temperature probes and BIs. The thermocouples and the BIs should
be placed at the same locations wherever possible. Special emphasis is placed on
those locations identified during cycle development studies as being difficult for
steam to penetrate/difficult to heat (cold spot determination). Such locations
typically include the interior of hoses, filter housings, large objects, filling
apparatus and items with multiple layers of protective wrapping.
The placement of temperature probes and BIs within the load must not enhance the
penetration of steam into the load item. Where the load includes multiple items of
the same configuration in the load (e.g. bags of stoppers), BIs should be placed in a
second item adjacent to that containing the thermocouple.
This is to prevent the presence of the thermocouple from enhancing the penetration of
steam to the BI.Where items in the load are unique, the BIs must be placed in the load
item near the probe and precautions taken to prevent enhanced steam penetration.
Heat penetration cycles performed, as part of an initial validation exercise
must be repeated several times, e.g. three times,to demonstrate consistency.
These studies should be performed using established load patterns, though a
minimum and maximum load may be used to represent each particular load
pattern for qualification purposes. The purpose of the heat penetration study is to
document that the load items (including the cold spot) receives the minimum
required pre-determined time at temperature/F0.
16
Fans or blowers are generally used to help assure uniform distribution of heat
throughout the chamber. Fan speed should be determined during validation and
thereafter periodically monitored to assure operation within the acceptable range.
Typical test during the validation of a dry heat oven include:
5.4.1.1 Empty Chamber Temperature Distribution
Temperature probes (thermocouples) are distributed throughout the empty
chamber (in free space) and a temperature profile is produced. A uniform
temperature profile is expected. A probe should be located next to the controlling
sensor. Note the come-up time to temperature and cool-down times, as these
should be consistent in an empty chamber.
5.4.1.2 Loaded Chamber Temperature Distribution and Heat Penetration
In dry heat applications loaded chamber mapping and heat penetration
studies must be performed. Typically, these studies may be performed at the
same time. Thermocouples must be distributed throughout the chamber (in
free space) for heat distribution information. Thermocouples must also be
placed inside of the container, equipment or component being treated for the
heat penetration information. The penetration thermocouples need to make
contact with the surface of the item. This is because, due to the mass of the item,
the time to reach sterilization/depyrogenation temperature can substantially lag
behind the temperature of the surrounding air.
Biological indicators or endotoxin-spiked vials should be located adjacent to the
penetration thermocouples. Heat penetration studies, conducted as part of the
initial validation, should be repeated several times (e.g. three times) to
demonstrate consistency.
Product containers should have container mapping performed similar to that
described for steam sterilization. Load patterns are important as air is a poor
conductor of heat and the distribution of mass can greatly affect heating
characteristics. Assigning a temperature profile requirement is more problematic
as the profile is load specific. The temperature profile for a specific load should
how good reproducibility
5.4.2 Dry Heat Tunnels
Validation of dry-heat tunnels is demonstrated by both temperature measurements
and inactivation of bacterial endotoxins (depyrogenation).
Similar studies to dry-heat ovens are performed, i.e., empty tunnel temperature
distribution and loaded tunnel endotoxin challenge. The temperature variation
within the sterilization/depyrogenation zone may be greater than seen in an oven.
Higher temperatures are usually selected - ranging from 270􀂃􀂃 - 350􀂃C, due to the
shorter exposure time required and the greater temperature variation. Points to consider
for physical measurements include:
Belt Speed - determines the exposure time
Temperature - determines the time required for inactivation
19
5.6 Validation Maintenance/Change Control/Revalidation
Validation of sterilization processes is not a one-time exercise. Validation
maintenance is a phrase that describes a number of activities that support the
ongoing validated state of a process. In the case of sterilization processes, routine
bioburden monitoring, preventive maintenance, calibration, cycle review and
approval and annual reviews are activities that make up validation maintenance.
Bioburden monitoring must take place for every batch of aseptically
produced drug product. The preventive maintenance program should provide
clear instructions on reporting any unusual observations or equipment
breakdowns/mechanical failures so that an evaluation can be made on impact to
the validated state. Cycle review and approval should be in accordance with
detailed SOPs that have a direct traceability to the qualification and validation
activities, set point parameters and acceptance ranges.
Chamber vacuum leak testing, air detector device performance (if so equipped),
Bowie-Dick type testing for steam penetration, thermometric testing for small
loads, and other types of testing or review that may be required by local
regulatory authority expectation or requirement should be understood and
implemented as appropriate. For example, steam quality testing is a requirement
of the UK authorities. These tests are also mentioned in the PDA Technical
Monograph #1 and FDA􀂶s Guideline on Drug Products Produced By Aseptic
Processing.
The change control program should ensure that technical experts and the Quality
Assurance Function assess any planned changes to the equipment, process, loads,
procedures or documentation as to whether the qualified or validated state may be
impacted by the change. Any additional work necessary to demonstrate the
ongoing validated state should be reviewed and approved as part of the change
control process. Sterilization processes are critical processes. Be vigilant in
assuring that any changes or repairs are fully assessed for potential impact
via the change control process. Perform a periodic assessment of the
potential cumulative effect of changes that individually may not be
significant enough to prompt revalidation but, taken together, indicate a
need to re qualify or revalidate.
Sterilization processes must be revalidated at least annually in the absence of
any change-driven revalidation. The revalidation can be a subset of the original
validation work. Some acceptable approaches include:
􀂇 Single runs rather than 3 consecutive runs are sufficient in the absence of
recurring problems
􀂇 The selection of a worst case load pattern for revalidation
􀂇 The revalidation of each type of cycle (e.g. cycle for stoppers, cycle for
filling parts, cycle for products, etc.) but not the revalidation of each cycle
loading pattern.
􀂇 The revalidation of the worst case loading pattern and one selected
loading pattern, with the rotation of the remaining loading patterns at
subsequent annual revalidations.
􀂇 The revalidation of the empty chamber, maximum and minimum loading